Although the development of relatively sophisticated techniques has enabled the study of methamphetamine-induced changes in the human brain, a more precise and thorough examination of underlying processes and mechanisms still requires the use of animal models. The studies proposed in this project will incorporate two animal models that provide paradigms to directly test specific hypotheses regarding pharmacodynamic and behavioral interactions between metharriphetamine (MA) and modafinil. Modafinil has been selected for study as a probe to modulate response inhibition in the human projects of the proposed Center, on the basis of its proven ability to improve inhibitory control in healthy human subjects. First, a pharmacokinetic model, using an intravenous methamphetamine delivery methodology that uniquely allows us to approximate the plasma MA profile that occurs in humans, will be used to assess the effects of modafinil on the in vivo neurotransmitter response to MA in MA-naTve and MA-experienced rats. The MA exposure will simulate conditions that parallel the quantitative features of the human MA exposure histories of participants in the human studies of the proposed Center. Microdialysis procedures will be used to assess the interactions between modafinil and MA on dopamine and norepinephrine dynamics in nucleus accumbens and prefrontal cortex. We will test the hypothesis that modafinil pretreatment will attenuate the nucleus accumbens dopamine response to MA (corresponding to an attenuated reinforcing effect), and will enhance the prefrontal cortex norepinephrine response to methamphetamine (corresponding to the cognitive effects). Second, a self-administration model and cue- and MA-induced reinstatement procedures will be used to examine the consequences of modafinil treatment on the reinforcing properties of MA and relapse to MA seeking in parallel to studies described in the human projects of the proposed Center. We will also investigate the neural circuitry responsible for modafinil's effects on MA self-administration by using local infusion of modafinil into specific brain target sites. We will test the hypothesis that modafinil pretreatment will reduce the reinforcing effects and decrease MA- and cue-induced reinstatement of methamphetamineseeking behavior. The results of these studies will provide a mechanistic foundation for the human data originating in the Center and may provide important new insight into potential new pharmacotherapies in the treatment of MA dependence.